DESCRIPTION (Adapted from applicant s abstract): The long-term objective of the proposed research is to define the molecular basis for the tissue specificity of group A beta-hemolytic streptococcal (GABHS) infection, and to define the role of emm gene products in pathogenesis. Although GABHS can thrive in almost any bodily tissue, it is the nasopharynx and impetigo lesion that serve as the primary sites of infection and principal reservoirs for transmission. The existence of distinct populations of throat and skin strains have long been suspected, but never proven on a molecular level. Recent studies have uncovered an organization that links different GABHS diseases (pharyngitis, impetigo, rheumatic fever) to the structure and function of emm genes, emm gene products, and emm-linked traits. The emm genes encode a diverse family of surface proteins, many of which are key virulence factors. The genetic distinction between pharyngeal and impetigo strains provides focus for addressing the molecular basis for the tissue-specificity of GABHS infection. Using genetically altered pharyngeal- and impetigo-derived GABHS, the contribution of emm genes and co-inherited traits to the tissue- specificity of GABHS infection will be established (Aim 1). Experimental models for pharyngeal infection (mouse) and impetigo (hamster) will be employed. If an emm gene product contributes to tissue-specific infectivity, the functional domain within M protein will be indentified by testing the relative infectivity of organisms that harbor mutated emm genes. If non- emm genes have a tissue-specific role, the contribution of two closely- linked genes (mga and scpA) will be explored (Aim 2). The role of the multiple emm gene products of impetigo isolates as targets of protective antibody and as mediators of the antiphagocytic effect will be assessed (Aim 3). This knowledge is crucial to an understanding of autoimmune diseases initiated by a tissue-restricted GABHS infection, e.g., rheumatic fever, and for the development of a vaccine that is both broad- based, and of high efficacy. If emm gene products define, at least in part, the tissue specificity of infection, than the horizontal transfer of emm genes that occurs between different GABHS strains may be an important mechanism for the emergence of new clones having unique pathogenic qualities and also, may lead to a change in the principal reservoir for transmission of that clone.